Steady-state function of the ubiquitous mammalian Na/H exchanger (NHE1) in relation to dimer coupling models with 2Na/2H stoichiometry

We describe the steady-state function of the ubiquitous mammalian Na/H exchanger (NHE)1 isoform in voltage-clamped Chinese hamster ovary cells, as well as other cells, using oscillating pH-sensitive microelectrodes to quantify proton fluxes via extracellular pH gradients. Giant excised patches could not be used as gigaseal formation disrupts NHE activity within the patch. We first analyzed forward transport at an extracellular pH of 8.2 with no cytoplasmic Na (i.e., nearly zero-trans). The extracellular Na concentration dependence is sigmoidal at a cytoplasmic pH of 6.8 with a Hill coefficient of 1.8. In contrast, at a cytoplasmic pH of 6.0, the Hill coefficient is <1, and Na dependence often appears biphasic. Results are similar for mouse skin fibroblasts and for an opossum kidney cell line that expresses the NHE3 isoform, whereas NHE1(-/-) skin fibroblasts generate no proton fluxes in equivalent experiments. As proton flux is decreased by increasing cytoplasmic pH, the half-maximal concentration (K(1/2)) of extracellular Na decreases less than expected for simple consecutive ion exchange models. The K(1/2) for cytoplasmic protons decreases with increasing extracellular Na, opposite to predictions of consecutive exchange models. For reverse transport, which is robust at a cytoplasmic pH of 7.6, the K(1/2) for extracellular protons decreases only a factor of 0.4 when maximal activity is decreased fivefold by reducing cytoplasmic Na. With 140 mM of extracellular Na and no cytoplasmic Na, the K(1/2) for cytoplasmic protons is 50 nM (pH 7.3; Hill coefficient, 1.5), and activity decreases only 25% with extracellular acidification from 8.5 to 7.2. Most data can be reconstructed with two very different coupled dimer models. In one model, monomers operate independently at low cytoplasmic pH but couple to translocate two ions in "parallel" at alkaline pH. In the second "serial" model, each monomer transports two ions, and translocation by one monomer allosterically promotes translocation by the paired monomer in opposite direction. We conclude that a large fraction of mammalian Na/H activity may occur with a 2Na/2H stoichiometry.

Rapid estimation of cartilage T2 based on double echo at steady state (DESS) with 3 Tesla

The double-echo-steady-state (DESS) sequence generates two signal echoes that are characterized by a different contrast behavior. Based on these two contrasts, the underlying T2 can be calculated. For a flip-angle of 90 degrees , the calculated T2 becomes independent of T1, but with very low signal-to-noise ratio. In the present study, the estimation of cartilage T2, based on DESS with a reduced flip-angle, was investigated, with the goal of optimizing SNR, and simultaneously minimizing the error in T2. This approach was validated in phantoms and on volunteers. T2 estimations based on DESS at different flip-angles were compared with standard multiecho, spin-echo T2. Furthermore, DESS-T2 estimations were used in a volunteer and in an initial study on patients after cartilage repair of the knee. A flip-angle of 33 degrees was the best compromise for the combination of DESS-T2 mapping and morphological imaging. For this flip angle, the Pearson correlation was 0.993 in the phantom study (approximately 20% relative difference between SE-T2 and DESS-T2); and varied between 0.429 and 0.514 in the volunteer study. Measurements in patients showed comparable results for both techniques with regard to zonal assessment. This DESS-T2 approach represents an opportunity to combine morphological and quantitative cartilage MRI in a rapid one-step examination.

Shifted Coupling of EEG Driving Frequencies and fMRI Resting State Networks in Schizophrenia Spectrum Disorders

INTRODUCTION: The cerebral resting state in schizophrenia is altered, as has been demonstrated separately by electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) resting state networks (RSNs). Previous simultaneous EEG/fMRI findings in healthy controls suggest that a consistent spatiotemporal coupling between neural oscillations (EEG frequency correlates) and RSN activity is necessary to organize cognitive processes optimally. We hypothesized that this coupling is disorganized in schizophrenia and related psychotic disorders, in particular regarding higher cognitive RSNs such as the default-mode (DMN) and left-working-memory network (LWMN). METHODS: Resting state was investigated in eleven patients with a schizophrenia spectrum disorder (n = 11) and matched healthy controls (n = 11) using simultaneous EEG/fMRI. The temporal association of each RSN to topographic spectral changes in the EEG was assessed by creating Covariance Maps. Group differences within, and group similarities across frequencies were estimated for the Covariance Maps. RESULTS: The coupling of EEG frequency bands to the DMN and the LWMN respectively, displayed significant similarities that were shifted towards lower EEG frequencies in patients compared to healthy controls. CONCLUSIONS: By combining EEG and fMRI, each measuring different properties of the same pathophysiology, an aberrant relationship between EEG frequencies and altered RSNs was observed in patients. RSNs of patients were related to lower EEG frequencies, indicating functional alterations of the spatiotemporal coupling. SIGNIFICANCE: The finding of a deviant and shifted coupling between RSNs and related EEG frequencies in patients with a schizophrenia spectrum disorder is significant, as it might indicate how failures in the processing of internal and external stimuli, as commonly seen during this symptomatology (i.e. thought disorders, hallucinations), arise.

Frequency-domain source localization shows state-dependent diazepam effects in 47-channel EEG

The topic of this study was to evaluate state-dependent effects of diazepam on the frequency characteristics of 47-channel spontaneous EEG maps. A novel method, the FFT-Dipole-Approximation (Lehmann and Michel, 1990), was used to study effects on the strength and the topography of the maps in the different frequency bands. Map topography was characterized by the 3-dimensional location of the equivalent dipole source and map strength was defined as the spatial standard deviation (the Global Field Power) of the maps of each frequency point. The Global Field Power can be considered as a measure of the amount of energy produced by the system, while the source location gives an estimate of the center of gravity of all sources in the brain that were active at a certain frequency. State-dependency was studied by evaluating the drug effects before and after a continuous performance task of 25 min duration. Clear interactions between drug (diazepam vs. placebo) and time after drug intake (before and after the task) were found, especially in the inferior-superior location of the dipole sources. It supports the hypothesis that diazepam, like other drugs, has different effects on brain functions depending on the momentary functional state of the brain. In addition to the drug effects, clearly different source locations and Global Field Power were found for the different frequency bands, replicating earlier reports (Michel et al., 1992).

State of the science on controversial topics: missing maxillary lateral incisors - a report of the Angle Society of Europe 2012 meeting

BACKGROUND The optimal long-term management of the congenitally missing maxillary lateral incisor continues to cause controversy within the specialty. The Angle Society of Europe meeting 2012 dedicated a day to address some of the current controversies relating to the management of these missing lateral incisors. FINDINGS The format of the day consisted of morning presentations and afternoon breakout sessions to discuss a variety of questions related to the management of missing lateral incisors. CONCLUSIONS The consensus viewpoint from this day was that the care of patients with congenitally missing lateral incisors is best achieved through a multi-disciplinary approach. The current evidence base is weak, and further well-designed, prospective trials are needed.

State of the science on controversial topics: orthodontic therapy and gingival recession (a report of the Angle Society of Europe 2013 meeting)

BACKGROUND Controversy exists in the literature between the role of orthodontic treatment and gingival recession. Whilst movement of teeth outside the alveolar bone has been reported as a risk factor for gingival recession, others have found no such association. FINDINGS The Angle Society of Europe devoted a study day to explore the evidence surrounding these controversies. The aim of the day was for a panel of experts to evaluate the current evidence base in relation to either the beneficial or detrimental effects of orthodontic treatment on the gingival tissue. CONCLUSIONS There remains a relatively weak evidence base for the role of orthodontic treatment and gingival recession and thus a need to undertake a risk assessment and appropriate consent prior to the commencement of treatment. In further prospective, well designed trials are needed.

Vordere Kreuzband-OP-Technik: «State of the Art» und Zukunft

Die Behandlung der vorderen Kreuzbandverletzung stellt die Chirurgie seit vielen Jahren vor grosse Herausforderungen. Die Geschichte der Kreuzbandchirurgie ist im Wesentlichen geprägt von der Suche nach dem perfekten Transplantat und dem operativen Fortschritt. In diesem Übersichtssartikel werden die aktuellen chirurgischen Strategien erörtert und ein Blick in die Zukunft gewagt.

A Targeted Survey for Scrapie in Jos Plateau State, Nigeria

Scrapie, a disease of sheep and goats with a progressive course and fatal outcome, has not been identified in Nigeria. Anecdotal scrapie reports by livestock workers abound. Livestock diseases like scrapie form huddles in livestock economics of countries. For 8 months we surveyed for scrapie targeting emergency/casualty slaughter sheep and goats in Jos, Nigeria. We clinically examined 510 sheep and 608 goats of local breeds, aged from 12 months to 5 years. In total 31 (5.10%) goats and no sheep were clinically suspicious for scrapie. Caudal brainstem tissues of suspect animals collected postmortem were analyzed for the disease specific form of the prion protein, PrPSc, using Bio-Rad’s TeSeE ELISA rapid test kit. No sample was positive for scrapie. Fluorescent antibody test for rabies and H&E staining on samples were carried out for differential diagnosis. These showed no pathological lesions indicative for neurological disease. While our findings do not exclude the presence of scrapie in Jos, we demonstrate that targeted sampling of small ruminants for neuroinfectious disease is feasible in developing countries, pointing to the possibility of implementing such a monitoring scheme in Nigeria to prevent economic losses in small ruminant livestock as scrapie caveats from endemic countries have shown.

Using state variables to model the response of tumour cells to radiation and heat: a novel multi-hit-repair approach

In order to overcome the limitations of the linear-quadratic model and include synergistic effects of heat and radiation, a novel radiobiological model is proposed. The model is based on a chain of cell populations which are characterized by the number of radiation induced damages (hits). Cells can shift downward along the chain by collecting hits and upward by a repair process. The repair process is governed by a repair probability which depends upon state variables used for a simplistic description of the impact of heat and radiation upon repair proteins. Based on the parameters used, populations up to 4-5 hits are relevant for the calculation of the survival. The model describes intuitively the mathematical behaviour of apoptotic and nonapoptotic cell death. Linear-quadratic-linear behaviour of the logarithmic cell survival, fractionation, and (with one exception) the dose rate dependencies are described correctly. The model covers the time gap dependence of the synergistic cell killing due to combined application of heat and radiation, but further validation of the proposed approach based on experimental data is needed. However, the model offers a work bench for testing different biological concepts of damage induction, repair, and statistical approaches for calculating the variables of state.

Static and dynamic characteristics of cerebral blood flow during the resting state in schizophrenia

Background: The cerebral network that is active during rest and is deactivated during goal-oriented activity is called the default mode network (DMN). It appears to be involved in self-referential mental activity. Atypical functional connectivity in the DMN has been observed in schizophrenia. One hypothesis suggests that pathologically increased DMN connectivity in schizophrenia is linked with a main symptom of psychosis, namely, misattribution of thoughts. Methods: A resting-state pseudocontinuous arterial spin labeling (ASL) study was conducted to measure absolute cerebral blood flow (CBF) in 34 schizophrenia patients and 27 healthy controls. Using independent component analysis (ICA), the DMN was extracted from ASL data. Mean CBF and DMN connectivity were compared between groups using a 2-sample t test. Results: Schizophrenia patients showed decreased mean CBF in the frontal and temporal regions (P < .001). ICA demonstrated significantly increased DMN connectivity in the precuneus (x/y/z = -16/-64/38) in patients than in controls (P < .001). CBF was not elevated in the respective regions. DMN connectivity in the precuneus was significantly correlated with the Positive and Negative Syndrome Scale scores (P < .01). Conclusions: In schizophrenia patients, the posterior hub-which is considered the strongest part of the DMN-showed increased DMN connectivity. We hypothesize that this increase hinders the deactivation of the DMN and, thus, the translation of cognitive processes from an internal to an external focus. This might explain symptoms related to defective self-monitoring, such as auditory verbal hallucinations or ego disturbances.

Twenty-three per cent of the Swiss adult population are using complementary medicine

Aim of the study: This study investigated the use among the Swiss adult population and the regional dissemination in Switzerland of various methods of complementary medicine (CM). It focused on CM methods that required visiting a physician or therapist and excluded e.g. over-the-counter drugs. Data and Methods: Data of the Swiss Health Survey 2007 were obtained from the Swiss Federal Statistical Office. This survey is performed every 5 years in a sample and is representative of the Swiss resident population from the age of 15 on. It consists of a telephone interview followed by a written questionnaire (2007: 18'760 and 14'432 respondents, respectively) and includes questions about people's state of health, general living conditions, lifestyle, health insurance and usage of health services. Users and non-users of CM were compared using logistic regression models. Results: 23.0 % of the Swiss adult population (women: 30.5 %, men: 15.2 %) used CM during the 12 months before the survey. Homeopathy (6.4 %), osteopathy (5.4 %) and acupuncture (4.9 %) were the most popular methods. The average number of treatments within 12 months for these three methods was 3.1 ± 3.6, 3.5 ± 3.3 and 6.6 ± 5.8, respectively. For treatments with homeopathy and acupuncture, medical practitioners were more commonly consulted than non-medical practitioners, for treatments with osteopathy no difference was found. By means of logistic regression, CM users and non-users were compared. There were significant differences in the use of CM between genders, age groups, levels of education and areas of living. Women, people aged 25 to 64 years, and people with higher levels of education used CM more commonly than men, people below 25 or above 64 years of age, or those with poorer education. Lake Geneva region and central Switzerland had a higher proportion of CM users than the other regions. Discussion: Almost one fourth of the Swiss adult population had used CM within 12 months before the survey. User profiles were comparable to those in other countries. Despite a generally lower self-perceived health status, elderly people were less likely to use CM. Reference: Klein SD, Frei-Erb M, Wolf U. Usage of complementary medicine across Switzerland. Results of the Swiss Health Survey 2007. Swiss Med Wkly. 2012;142:w13666.

Twenty-three per cent of the Swiss adult population are using complementary medicine

Aim of the study Various forms of complementary medicine (CM) play an important role in the Swiss health care system, they are appreciated by a majority of the population and mostly used complementarily rather than alternatively to conventional medicine. This study investigates, how many people in Switzerland are actually being treated with CM, and what the most popular methods of CM are. Data Data of the Swiss Health Survey 2007 were obtained from the Swiss Federal Statistical Office. This survey is performed every 5 years amongst a sample of the Swiss resident population above 15 years of age. It consists of a telephone interview followed by a written questionnaire (2007: 18'760 and 14'432 respondents, respectively) and includes questions about people's state of health, general living conditions, lifestyle, health insurance and usage of health services. Results 23.0% of the Swiss adult population (women: 30.5%, men: 15.2%) used CM during the 12 months before the survey. Homeopathy (6.4%), osteopathy (5.4%) and acupuncture (4.9%) were the most popular methods. The average number of treatments within 12 months for these three methods was 3.1, 3.5 and 6.6, respectively. For treatments with homeopathy and acupuncture, medical practitioners were more commonly consulted than non-medical practitioners, for treatments with osteopathy no difference was found. By means of logistic regression, CM users and non-users were compared. There were significant differences in the use of CM between genders, age groups, levels of education and areas of living. Women, people aged 25 to 64 years, and people with higher education used CM more commonly than men, people below 25 or above 64 years of age, or those with poorer education. Lake Geneva region and central Switzerland had a higher proportion of CM users than the other regions. Discussion While 2 years ago, 67.0% of the Swiss population approved a referendum in favour of CM, we find that 23.0% are in fact using it. Current political discussions focus on effectiveness, cost effectiveness and suitability of CM to decide which methods should be permanently covered by the basic health insurance.

State-of-the-art aortic imaging: part I - fundamentals and perspectives of CT and MRI

Over the last two decades, imaging of the aorta has undergone a clinically relevant change. As part of the change non-invasive imaging techniques have replaced invasive intra-arterial digital subtraction angiography as the former imaging gold standard for aortic diseases. Computed tomography (CT) and magnetic resonance imaging (MRI) constitute the backbone of pre- and postoperative aortic imaging because they allow for imaging of the entire aorta and its branches. The first part of this review article describes the imaging principles of CT and MRI with regard to aortic disease, shows how both technologies can be applied in every day clinical practice, offering exciting perspectives. Recent CT scanner generations deliver excellent image quality with a high spatial and temporal resolution. Technical developments have resulted in CT scan performed within a few seconds for the entire aorta. Therefore, CT angiography (CTA) is the imaging technology of choice for evaluating acute aortic syndromes, for diagnosis of most aortic pathologies, preoperative planning and postoperative follow-up after endovascular aortic repair. However, radiation dose and the risk of contrast induced nephropathy are major downsides of CTA. Optimisation of scan protocols and contrast media administration can help to reduce the required radiation dose and contrast media. MR angiography (MRA) is an excellent alternative to CTA for both diagnosis of aortic pathologies and postoperative follow-up. The lack of radiation is particularly beneficial for younger patients. A potential side effect of gadolinium contrast agents is nephrogenic systemic fibrosis (NSF). In patients with high risk of NSF unenhanced MRA can be performed with both ECG- and breath-gating techniques. Additionally, MRI provides the possibility to visualise and measure both dynamic and flow information.